How doctors discuss major interventions with high risk patients: an observational study.

OBJECTIVE: To investigate the difficulties doctors face in discussing treatment options with patients with acute, life threatening illness and major comorbidities. DESIGN: Observational study of doctor-patient interviews based on a standardised clinical scenario involving high risk surgery in a hypothetical patient (played by an actor) with serious comorbidities. PARTICIPANTS: 30 trainee doctors 3-5 years after graduation. MAIN OUTCOME MEASURES: Adequacy of coverage of various aspects was scored from 3 (good) to 0 (not discussed). RESULTS: The medical situation was considered to be well described (median score 2.7 (interquartile range 2.1-3.0)), whereas the patient's functional status, values, and fears were poorly or minimally addressed (scores 0.5 (0.0-1.0), 0.5 (0.0-1.0), and 0.0 (0.0-1.5), respectively; all P < 0.001 v score for describing the medical situation). Twenty nine of the doctors indicated that they wished to include the patient's family in the discussion, but none identified a preferred surrogate decision maker. Six doctors suggested that the patient alone should speak with his family to reach a decision without the doctor being present. The doctors were reluctant to give advice, despite it being directly requested: two doctors stated that a doctor could not give advice, while 17 simply restated the medical risks, without advocating any particular course. Of the 11 who did offer advice, eight advocated intervention. CONCLUSIONS: Doctors focused on technical medical issues and placed much less emphasis on patient issues such as functional status, values, wishes, and fears. This limits doctors' ability to offer suitable advice about treatment options. Doctors need to improve their communication skills in this difficult but common clinical situation.

Roles of two conserved cysteine residues in the activation of human adenovirus proteinase.

The roles of two conserved cysteine residues involved in the activation of the adenovirus proteinase (AVP) were investigated. AVP requires two cofactors for maximal activity, the 11-amino acid peptide pVIc (GVQSLKRRRCF) and the viral DNA. In the AVP-pVIc crystal structure, conserved Cys104 of AVP has formed a disulfide bond with conserved Cys10 of pVIc. In this work, pVIc formed a homodimer via disulfide bond formation with a second-order rate constant of 0.12 M(-1) s(-1), and half of the homodimer could covalently bind to AVP via thiol-disulfide exchange. Alternatively, monomeric pVIc could form a disulfide bond with AVP via oxidation. Regardless of the mechanism by which AVP becomes covalently bound to pVIc, the kinetic constants for substrate hydrolysis were the same. The equilibrium dissociation constant, K(d), for the reversible binding of pVIc to AVP was 4.4 microM. The K(d) for the binding of the mutant C10A-pVIc was at least 100-fold higher. Surprisingly, the K(d) for the binding of the C10A-pVIc mutant to AVP decreased at least 60-fold, to 6.93 microM, in the presence of 12mer ssDNA. Furthermore, once the mutant C10A-pVIc was bound to an AVP-DNA complex, the macroscopic kinetic constants for substrate hydrolysis were the same as those exhibited by wild-type pVIc. Although the cysteine in pVIc is important in the binding of pVIc to AVP, formation of a disulfide bond between pVIc and AVP was not required for maximal stimulation of enzyme activity by pVIc.

Discovery of a new inhibitor lead of adenovirus proteinase: steps toward selective, irreversible inhibitors of cysteine proteinases.

Using the computer docking program EUDOC, in silico screening of a chemical database for inhibitors of human adenovirus cysteine proteinase (hAVCP) identified 2,4,5,7-tetranitro-9-fluorenone that selectively and irreversibly inhibits hAVCP in a two-step reaction: reversible binding (Ki = 3.09 microM) followed by irreversible inhibition (ki = 0.006 s(-1)). The reversible binding is due to molecular complementarity between the inhibitor and the active site of hAVCP, which confers the selectivity of the inhibitor. The irreversible inhibition is due to substitution of a nitro group of the inhibitor by the nearby Cys122 in the active site of hAVCP. These findings suggest a new approach to selective, irreversible inhibitors of cysteine proteinases involved in normal and abnormal physiological processes ranging from embryogenesis to apoptosis and pathogen invasions.

Breast and cervical cancer screening interventions: an assessment of the literature.

An extensive body of intervention research to promote breast and cervical cancer screening has accumulated over the last three decades, but its coverage and comprehensiveness have not been assessed. We evaluated published reports of these interventions and propose a framework of critical elements for authors and researchers to use when contributing to this literature. We identified all articles describing breast and cervical cancer screening interventions published between January 1960 and May 1997 in the United States and abstracted specified critical elements in the broad areas of: (a) needs assessment; (b) intervention study design; and (c) analysis methods and study outcomes from each article using a template developed for that purpose. Fifty-eight studies met our criteria for inclusion. Thirty-eight focused exclusively on breast cancer screening, 7 promoted cervical cancer screening, and 13 were designed to promote screening for both cancers. The amount of detail reported varied among the 58 studies. All studies reported the outcome measures used to assess the effectiveness of the intervention, yet only 40% of the studies reported the investigators' original hypotheses or research questions. Needs assessment data were reported in 84% of the studies. Data sources ranged from national surveys to local intervention baseline surveys. Population characteristics reported also varied, with most studies reporting age and race of the study population (78 and 71%, respectively), and fewer studies reporting income and education (53 and 38%, respectively). As the field of behavioral intervention research progressed, we found that more recent studies included and reported many of the parameters we had identified as critical. If this trend continues, it will enhance the reproducibility of studies, enable comparisons between interventions, and provide a reference point for measuring progress in this area. To facilitate this trend toward uniform reporting, we propose an evaluative framework of critical elements for authors to use when developing and reporting their research. The comprehensive assessment of literature that this article provides should be useful background to investigators planning and reporting cancer control interventions, to funding agencies choosing and guiding quality research, and to publishers to help them enhance the quality and utility of their publications.

Anaesthesia for a patient undergoing thoracoscopic assisted trans-hiatal oesophagectomy.

We describe the anaesthetic management of an elderly woman who underwent thoracoscopically assisted trans-hiatal oesophagectomy. One-lung ventilation with insufflation of carbon dioxide was necessary for adequate surgical access. Potential intra-operative problems included hypoxaemia during one-lung ventilation, mediastinal shift and inadvertent damage to mediastinal structures.

Diabetic and age-related enhancement of collagen-linked fluorescence in cortical bones of rats.

Nonenzymatic collagen cross-linking occurs in a variety of connective tissues as a result of formation of advanced glycosylation end products. Diabetes and aging significantly increase levels of nonenzymatic collagen cross-linking in connective tissues. This study was undertaken to determine whether nonenzymatic collagen cross-linking occurs in rat cortical bone and if these levels are increased in diabetic and aged rats. Collagen-linked fluorescence, a measurement of nonenzymatic collagen cross-linking, was significantly increased in rat cortical bone with diabetes and age. In addition, incubation of bone powder with glucose resulted in a similar increase in collagen-linked fluorescence. These changes in bone collagen may contribute to alterations observed in bone with diabetes and age by influencing bone cell function and the ability of the matrix to be responsive to bone cells.

The impact of breakthrough clinical trials on survival in population based tumor registries.

Three statistical models are developed to study the impact that two breakthrough clinical trials (MOPP for Hodgkin's disease and PVB for disseminated testicular cancer) had on survival in the Connecticut tumor registry and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry program. A segmented regression model is used in conjunction with the Cox semi-parametric proportional hazards model, as well as the parametric Weibull and exponential cure models. These models allow us to determine approximately when survival first began to improve dramatically, indicating that improved treatments had become available, and how long it took for survival to level off again indicating that the full population survival impact had been realized. In addition, the degree to which the parametric models fit allows us to determine if the survival improvements occur within a parametric family. Results of the modelling indicate that dissemination took approximately 11 years in Hodgkin's disease while only 3 years in disseminated testicular cancer. In both disease sites survival first broke with prior trends between the time that the breakthrough trial started and its publication, indicating that earlier moderately successful 'precursor' trials with combination chemotherapy may have initiated the improved population survival trends. Reasons for the difference in dissemination time in the two cancer sites are examined in order to understand what factors may be responsible for the speed of dissemination and effective utilization of new therapies.

Direct effects of calcium channel blockers on duodenal calcium transport in vivo.

The direct effects of verapamil, diltiazem and nifedipine on duodenal calcium transport were assessed in rats by the in vivo ligated loop technique, using luminal calcium concentrations at which active and passive transport mechanisms predominate (2 and 50 mM Ca, respectively). At 2 mM Ca, addition of verapamil (0.3-10 mM) to the luminal solution caused a concentration-dependent decrease in calcium lumen-to-plasma uptake and an increase in calcium plasma-to-lumen translocation, such that at 10 mM verapamil there was a net secretion of calcium into the duodenal lumen. In contrast, nifedipine (0.3-3 mM) was without effect on calcium transport, and diltiazem reduced calcium lumen-to-plasma uptake and net calcium absorption only at 10 mM, without influencing plasma-to-lumen translocation. The verapamil-induced increase in calcium plasma-to-lumen translocation was abolished by bile duct ligation. Calcium transport was unaffected by any calcium channel blocker at 50 mM luminal calcium. Thus, verapamil can directly influence active calcium translocation in the intestine, in vivo, and may affect calcium homeostasis during chronic oral treatment with this drug.